The present invention is novel compounds which are indoles substituted at the 3-position with thiazolidinone, oxazolidinone, or imidazolidinones, and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use thereof. The invention compounds are now found to have activity as inhibitors of one or both of cyclooxygenase and 5-lipoxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever, and the like. Thus, the present invention is also a pharmaceutical composition or method of use thereof.
Although indoles are known antiinflammatory agents and various 2 substituted thiazolidinones, oxazolidinones, or imidazolidinones are known as useful substituents in other antiinflammatory agents, for example, with 3,5-di-tertiary-butyl-4-hydroxyphenyl groups as disclosed in EP Application No. 89 109406.2 and U.S. patent application Ser. No. 499,937 (incorporated herein by reference), the present combination of ring systems, substituents and moieties is not among those previously known. Other compounds having ring systems including various thiazolidinones, oxazolidinones, and imidazolidinones and references disclosing such related compounds are found in the following references as well as:
Japanese patent application J6 1012-674-A (Derwent Abstract 86-059691/09) discloses an imidazolidinone compound of the structure ##STR1## with utility as an antiallergic. It lacks the indole structure present in the compounds claimed herein.
Denmark Patent Application DE 3713-094-A (Derwent Abstract 87-307841/44) discloses benzylidene compounds of which compounds of the structure ##STR2## are included, wherein R is 1-18C straight chain alkyl or 3-18C branched or cyclic alkyl. These compounds lack the indole structure present in the compounds claimed herein.
U.S. Pat. No. 4,464,382 discloses compounds of the formula ##STR3## wherein (1) R.sup.1 and R.sup.2 are taken together to represent a tetramethylene or pentamethylene group, (II) R.sup.1 represents a hydrogen atom, and R.sup.2 represents (1) a cycloalkyl or cycloalkenyl group of 4-7 carbon atoms which is unsubstituted or substituted by at least one alkyl group of 1-4 carbon atoms, (2) an anthryl or naphthyl group, (3) a phenyl group which is unsubstituted or substituted, p. 2 (4) a heterocyclic group containing at least one of nitrogen, oxygen, and sulfur atoms which is unsubstituted or substituted (5) a ##STR4## group (wherein R.sup.4 represents a hydrogen atom, a halogen atom, phenyl group, or an alkyl group of 1-5 carbon atoms; and R.sup.5 represents a hydrogen atom, a phenyl group, or an alkyl group of 1-5 carbon atoms) or ##STR5## group; or (III) R.sup.1 and R.sup.2, which may be the same or different with each other, each represents a phenyl group which is unsubstituted or substituted; and R.sup.3 represents a hydrogen atom, an alkyl group of 1-12 carbon atoms, an aralkyl group of 7-13 carbon atoms, a cycloalkyl or cycloalkenyl group of 4-7 carbon atoms which is unsubstituted or substituted by at least one alkyl group of 1-4 carbon atoms, or a phenyl group which is unsubstituted or substituted, possess a strong inhibitory activity on aldose reductase but lack the indole structure.
Bosin and Campaigne, Intnt'l. J. of Sulfur Chem., Vol. 2, p. 262 (1972) disclose compounds of the formula ##STR6## wherein X is F or Cl. These compounds also lack the indole structure of the present invention.
Compounds are disclosed having an indole system substituted at the 2- or 3-position in European Publication Number 279,263 and U.S. Pat. No. 4,464,382.
U.S. Pat. No. 3,161,654 discloses an indole ring system substituted through the nitrogen with p-chlorobenzoacyl.
These compounds may be distinguished from the compounds of the invention herein by the absence of oxazolidinone, imidazolidinone, or thiazolidinone structures or by the unique combination of indole substituents disclosed here.
Within these disclosures are uses for treating inflammation as are found here, but the differences between known compounds and the present compounds are readily apparent, with no teaching to make obvious that such differences would also be useful for treatment of the conditions taught here.
Thus, the disclosed compounds do not contain the combination of ring systems and substituents which is the present invention.